tbuckley/cabot-search huggingface dataset:
Barrett Esophagus
Authors: Prateek Sharma
Journal: JAMA (2022)

Importance Barrett esophagus is characterized by the replacement of normal esophageal squamous cell epithelium with columnar metaplasia and affects approximately 5% of people in the US and approximately 1% worldwide. Approximately 3% to 5% of patients with Barrett esophagus will be diagnosed with esophageal adenocarcinoma in their lifetime. Observations Barrett esophagus affects approximately 2.3% to 8.3% of people with gastroesophageal reflux disease (GERD) and approximately 1.2% to 5.6% of people without GERD. Characteristics associated with Barrett esophagus include older age (prevalence of approximately 1.1% in individuals older than 50 years compared with 0.3% in those 50 years or younger), male sex, and smoking (prevalence of approximately 12% in people who smoke cigarettes compared with 1.1% in those who do not smoke cigarettes). The histopathology of Barrett esophagus progresses from metaplasia to dysplasia and, without treatment, can progress to adenocarcinoma. People with Barrett esophagus have approximately a 0.2% to 0.5% annual rate of developing esophageal adenocarcinoma. Management of Barrett esophagus primarily consists of acid-suppressive medications to reduce underlying GERD symptoms and surveillance endoscopy every 3 to 5 years. In patients with Barrett esophagus and dysplasia or early cancer, endoscopic therapy consisting of resection and ablation successfully treats 80% to 90% of patients. Conclusions and Relevance Barrett esophagus affects approximately 5% of people in the US and approximately 1% worldwide and is associated with an increased risk of esophageal adenocarcinoma. First-line therapy for Barrett esophagus consists of proton-pump inhibitors for control of reflux symptoms, but their role in chemoprevention is unclear. Surveillance with upper endoscopy is recommended by practice guidelines to monitor for progression to esophageal adenocarcinoma, but randomized clinical trials are lacking.
Urine eosinophil‐derived neurotoxin: A potential marker of activity in select eosinophilic disorders
Authors: Michelle A. Makiya, Paneez Khoury, Fei Li Kuang, Alexis Dominique Mata, Sana Mahmood, Abbie Bowman, David Espinoza, Nicholas Kovacs, Thomas Brown, Nicole Holland, Lauren Wetzler, JeanAnne M. Ware, Anne‐Marie Dyer, Praveen Akuthota, Bruce S. Bochner, Vernon M. Chinchilli, Gerald J. Gleich, Carol Langford, Peter A. Merkel, Ulrich Specks, Peter F. Weller, Michael E. Wechsler, Calman Prussin, Michael P. Fay, Amy D. Klion
Journal: Allergy (2022)

Biomarkers of eosinophilic disease activity, especially in the context of novel therapies that reduce blood eosinophil counts, are an unmet need. Absolute eosinophil count (AEC) does not accurately reflect tissue eosinophilia or eosinophil activation. Therefore, the aims of this study were to compare the reliability of plasma and urine eosinophil major basic protein 1, eosinophil cationic protein, eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase measurement and to evaluate the usefulness of eosinophil granule protein (EGP) measurement for the assessment of disease activity in patients with eosinophil-associated diseases treated with mepolizumab, benralizumab, or dexpramipexole.
Spatiotemporal Delivery of pBMP2 and pVEGF by a Core–Sheath Structured Fiber‐Hydrogel Gene‐Activated Matrix Loaded with Peptide‐Modified Nanoparticles for Critical‐Sized Bone Defect Repair
Authors: Shan He, Ju Fang, Chuanxin Zhong, Min Wang, Fuzeng Ren
Journal: Advanced Healthcare Materials (2022)

Abstract The clinical translation of bioactive scaffolds for the treatment of large segmental bone defects remains a grand challenge. The gene‐activated matrix (GAM) combining gene therapy and tissue engineering scaffold offers a promising strategy for the restoration of structure and function of damaged or dysfunctional tissues. Herein, a gene‐activated biomimetic composite scaffold consisting of an electrospun poly( ε ‐caprolactone) fiber sheath and an alginate hydrogel core which carried plasmid DNA encoding bone morphogenetic protein 2 (pBMP2) and vascular endothelial growth factor (pVEGF), respectively, is developed. A peptide‐modified polymeric nanocarrier with low cytotoxicity and high efficiency serves as the nonviral DNA delivery vector. The obtained GAM allows spatiotemporal release of pVEGF and pBMP2 and promotes osteogenic differentiation of preosteoblasts in vitro. In vivo evaluation using a critical‐sized segmental femoral defect model in rats shows that the dual gene delivery system can significantly accelerate bone healing by activating angiogenesis and osteogenesis. These findings demonstrate the effectiveness of the developed dual gene‐activated core–sheath structured fiber‐hydrogel composite scaffold for critical‐sized bone defect regeneration and the potential of cell‐free scaffold‐based gene therapy for tissue engineering.
Inflammatory Bowel Disease
Authors: Daniel K. Podolsky
Journal: New England Journal of Medicine (2002)

Clinical experience has suggested that Crohn's disease and ulcerative colitis constitute distinct, if not discrete, entities. However, whether these conditions are fundamentally different or are part of a mechanistic continuum is a question with both conceptual and practical implications for management. This review summarizes current understanding of the mechanisms underlying the major forms of inflammatory bowel disease and discusses approaches to therapy.
Radiotherapy for Bone Pain
Authors: P R Needham, N P Mithal, P J Hoskin
Journal: Journal of the Royal Society of Medicine (1994)

Painful bone metastases are a common problem for cancer patients. Although current evidence supports the use of a single fraction of radiotherapy as the treatment of choice, many radiotherapists, for a variety of reasons, continue to use fractionated regimens. Over one six month period 105 patients received external beam irradiation for painful bone metastases at the Royal London Hospital (RLH). Thirty-one per cent of the patients were aged 70 or over. The treatment of 97 of these patients was assessed. They had a total of 280 sites treated over the course of their disease. Fifty-nine per cent of sites treated received a fractionated course of radiotherapy. Site significantly influenced fractionation. Overall response rates of 82% were achieved. Fractionation did not appear to influence this. Ten patients received large field irradiation. Fifteen patients had five or more sites irradiated, of whom only one received hemibody irradiation.
A framework for digital health equity
Authors: Safiya Richardson, Katharine Lawrence, Antoinette M. Schoenthaler, Devin Mann
Journal: npj Digital Medicine (2022)

Abstract We present a comprehensive Framework for Digital Health Equity, detailing key digital determinants of health (DDoH), to support the work of digital health tool creators in industry, health systems operations, and academia. The rapid digitization of healthcare may widen health disparities if solutions are not developed with these determinants in mind. Our framework builds on the leading health disparities framework, incorporating a digital environment domain. We examine DDoHs at the individual, interpersonal, community, and societal levels, discuss the importance of a root cause, multi-level approach, and offer a pragmatic case study that applies our framework.
Body weight changes and duration of estrogen exposure modulate the evolution of hepatocellular adenomas after contraception discontinuation
Authors: Alix Demory, Jean‐Marie Péron, Julien Calderaro, Janick Selves, Fatima‐Zohra Mokrane, Giuliana Amaddeo, Valérie Paradis, Marianne Ziol, Olivier Sutter, Lorraine Blaise, Nathalie Ganne‐Carrié, Valérie Vilgrain, François Cauchy, Jessica Zucman‐Rossi, Maxime Ronot, Jean‐Charles Nault
Journal: Hepatology (2022)

The natural history of hepatocellular adenomas (HCAs) remains to be better described, especially in nonresected patients. We aim to identify the predictive factors of HCA evolution after estrogen-based contraception discontinuation.We retrospectively included patients with a histological diagnosis of HCA from three centers. Clinical, radiological, and pathological data were collected to identify predictive factors of radiological evolution per Response Evaluation Criteria in Solid Tumors, version 1.1, and occurrence of complications (bleeding, malignant transformation). We built a score using variables that modulate estrogen levels: body mass index and duration of estrogen-based contraception. An external cohort was used to validate this score. 183 patients were included in the cohort, including 161 women (89%) using estrogen-based contraception for a median of 12 years. Thirty percent of patients had at least one HNF1A -inactivated HCA, 45.5% at least one inflammatory HCA, and 11% at least one HCA with activation of β-catenin (bHCA). Twenty-one symptomatic bleedings (11%) and eleven malignant transformations (6%) occurred. Ages < 37 years old ( p = 0.004) and HCA > 5 cm at imaging were independently associated with symptomatic bleeding ( p = 0.003), whereas a bHCA was associated with malignant transformation ( p < 0.001). After a median follow-up of 5 years, radiological regression was observed in 31%, stabilization in 47%, and progression in 22% of patients. Weight loss was associated with regression ( p < 0.0001) and weight gain with progression ( p = 0.02). The estrogen exposure score predicted radiological regression (odds ratio, 2.33; confidence interval 95%, 1.29-4.19; p = 0.005) with a linear relationship between the rate of estrogen exposure and the probability of regression. This result was confirmed in an external cohort of 72 female patients ( p = 0.003).Weight variation is strongly associated with radiological evolution after oral contraception discontinuation. A score of estrogen exposure, easily assessable in clinical practice at diagnosis, predicts regression of HCA.
HER2 drives lung fibrosis by activating a metastatic cancer signature in invasive lung fibroblasts
Authors: Xue Liu, Yan Geng, Jiurong Liang, Ana Lucia Coelho, Changfu Yao, Nan Deng, Yizhou Wang, Kristy Dai, Guanling Huang, Ting Xie, Ningshan Liu, Simon C. Rowan, Forough Taghavifar, Vrishika Kulur, Zhenqiu Liu, Barry R. Stripp, Cory M. Hogaboam, Dianhua Jiang, Paul W. Noble
Journal: The Journal of Experimental Medicine (2022)

Progressive tissue fibrosis, including idiopathic pulmonary fibrosis (IPF), is characterized by excessive recruitment of fibroblasts to sites of tissue injury and unremitting extracellular matrix deposition associated with severe morbidity and mortality. However, the molecular mechanisms that control progressive IPF have yet to be fully determined. Previous studies suggested that invasive fibroblasts drive disease progression in IPF. Here, we report profiling of invasive and noninvasive fibroblasts from IPF patients and healthy donors. Pathway analysis revealed that the activated signatures of the invasive fibroblasts, the top of which was ERBB2 (HER2), showed great similarities to those of metastatic lung adenocarcinoma cancer cells. Activation of HER2 in normal lung fibroblasts led to a more invasive genetic program and worsened fibroblast invasion and lung fibrosis, while antagonizing HER2 signaling blunted fibroblast invasion and ameliorated lung fibrosis. These findings suggest that HER2 signaling may be a key driver of fibroblast invasion and serve as an attractive target for therapeutic intervention in IPF.
Tom Nolan’s research reviews—18 August 2022
Authors: Tom Nolan
Journal: BMJ (2022)

New clinical presentations of monkeypoxWhat are the clinical outcomes for people diagnosed with monkeypox in the current outbreak?New research from sexual health centres in South London (BMJ 2022;378:e072410) identifies new clinical presentations of monkeypox in this current outbreak, including rectal pain and penile oedema.
TGF-β promotes stem-like T cells via enforcing their lymphoid tissue retention
Authors: Chaoyu Ma, Liwen Wang, Wei Liao, Yong Liu, Shruti Mishra, Guo Li, Xin Zhang, Yuanzheng Qiu, Qianjin Lu, Nu Zhang
Journal: The Journal of Experimental Medicine (2022)

Stem-like CD8+ T cells sustain the antigen-specific CD8+ T cell response during chronic antigen exposure. However, the signals that control the maintenance and differentiation of these cells are largely unknown. Here, we demonstrated that TGF-β was essential for the optimal maintenance of these cells and inhibited their differentiation into migratory effectors during chronic viral infection. Mechanistically, stem-like CD8+ T cells carried a unique expression pattern of α4 integrins (i.e., α4β1hi and α4β7lo) controlled by TGF-β. In the absence of TGF-β signaling, greatly enhanced expression of migration-related markers, including altered expression of α4 integrins, led to enhanced egress of stem-like CD8+ T cells into circulation accompanied by further differentiation into transitional states. Blocking α4 integrin significantly promoted their lymphoid tissue retention and therefore partially rescued the defective maintenance of Tcf-1+ subset in the absence of TGF-β signaling. Thus, TGF-β promotes the maintenance and inhibits the further differentiation of stem-like T cells at least partially via enforcing their lymphoid tissue residency.
TGF-β regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection
Authors: Yinghong Hu, William H. Hudson, Haydn T. Kissick, Christopher B. Medina, Antonio P. Baptista, Chaoyu Ma, Wei Liao, Ronald N. Germain, Shannon J. Turley, Nu Zhang, Rafi Ahmed
Journal: The Journal of Experimental Medicine (2022)

Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-β in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice. We found that TGF-β signaling was not essential for the generation of the stem-like CD8 T cells but was critical for maintaining the stem-like state and quiescence of these cells. TGF-β regulated the unique transcriptional program of the stem-like subset, including upregulation of inhibitory receptors specifically expressed on these cells. TGF-β also promoted the terminal differentiation of exhausted CD8 T cells by suppressing the effector-associated program. Together, the absence of TGF-β signaling resulted in significantly increased accumulation of effector-like CD8 T cells. These findings have implications for immunotherapies in general and especially for T cell therapy against chronic infections and cancer.
Donor Human Milk Use in Advanced Neonatal Care Units — United States, 2020
Authors: Ellen O. Boundy, Erica H. Anstey, Jennifer M. Nelson
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Approximately 50,000 infants are born in the United States each year with very low birthweight (VLBW) (<1,500 g).* Benefits of human milk to infants with VLBW include decreased risk for necrotizing enterocolitis, a serious illness resulting from inflammation and death of intestinal tissue that occurs most often in premature infants, especially those who are fed formula rather than human milk; late-onset sepsis; chronic lung disease; retinopathy of prematurity; and neurodevelopmental impairment (1). When mother's own milk is unavailable or insufficient, pasteurized donor human milk (donor milk) plus a multinutrient fortifier is the first recommended alternative for infants with VLBW (2). CDC's 2020 Maternity Practices in Infant Nutrition and Care (mPINC) survey was used to assess practices for donor milk use in U.S. advanced neonatal care units of hospitals that provide maternity care (3). Among 616 hospitals with neonatal intensive care units (level III or IV units),† 13.0% reported that donor milk was not available for infants with VLBW; however, approximately one half (54.7%) reported that most (≥80%) infants with VLBW do receive donor milk. Donor milk availability for infants with VLBW was more commonly reported among hospitals with a level IV unit, higher annual birth volume, location in the Midwest and Southwest regions, nonprofit and teaching status, and those designated Baby-Friendly.§ Addressing hospitals' barriers to providing donor milk could help ensure that infants with VLBW receive donor milk when needed and help reduce morbidity and mortality in infants with VLBW (1,4).
Iron-based nanoscale coordination polymers synergistically induce immunogenic ferroptosis by blocking dihydrofolate reductase for cancer immunotherapy
Authors: Yue Yu, Zhusheng Huang, Qian Chen, Zhicheng Zhang, Haojie Jiang, Rong Gu, Yitao Ding, Yiqiao Hu
Journal: Biomaterials (2022)

Iron is indispensable for cancer cell survival and cancer cells are more vulnerable to ferroptosis than normal cells. Ferroptosis holds promise for overcoming chemoresistance and inducing tumor immunogenic cell death, which offers new possibilities for cancer immunotherapy. However, the prevalence of immunogenic ferroptosis in cancer cells is diminished because of the high levels of reducing substances within tumor microenvironments. Ferroptosis-needed iron is overdose for livings, which is also an obstacle for effective immune responses. In this study, we construct self-assembled carrier-free nanoscale coordination polymers based on iron and methotrexate (MFe-NCPs). The low-dose-iron-induced immunogenic ferroptosis is obviously enhanced by methotrexate via inhibiting dihydrofolate reductase and abating substance reduction, respectively. Of note, MFe-NCPs sequentially promoted antigen presentation, immune activation, T cell infiltration and boosted the therapeutic effect of immune checkpoint blockade therapy.
Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial
Authors: Qian Jiang, Zongru Li, Yazhen Qin, Weiming Li, Na Xu, Bingcheng Liu, Yanli Zhang, Li Meng, Huanling Zhu, Xin Du, Suning Chen, Yang Liang, Yu Hu, Xiaoli Liu, Yongping Song, Lichuang Men, Zi Chen, Qian Niu, Hengbang Wang, Ming Lu, Dajun Yang, Yifan Zhai, Xiaojun Huang
Journal: Journal of Hematology & Oncology (2022)

Abstract Background BCR-ABL1 T315I mutations confer resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Olverembatinib is a new potent BCR-ABL1 TKI with preclinical activity against T315I-mutated CML. In phase 1/2 studies, we explored the safety and efficacy of olverembatinib in Chinese adults with TKI-resistant CML in the chronic phase (CML-CP) and accelerated phase (CML-AP). Methods In the phase 1 study, olverembatinib was orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg, and we evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics of olverembatinib. In the phase 2 studies, olverembatinib was administered at the RP2D of 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response by the end of Cycle 12 in CML-CP and CML-AP, respectively. Fine and Gray's hazard models were used to identify covariates associated with responses. Results A total of 165 patients (&gt; 80.0% of whom had received ≥ 2 TKIs) were enrolled in this study. Among 127 patients with CML-CP, the 3-year cumulative incidences of achieving MCyR, complete cytogenetic response (CCyR), major molecular response (MMR), MR 4.0 , and MR 4.5 were 79.0, 69.0, 56.0, 44.0 and 39.0%, respectively. The highest response rates were observed in patients with a single T315I mutation. Among 38 patients with CML-AP, the 3-year cumulative incidences of achieving MCyR, CCyR, MMR, MR 4.0 , and MR 4.5 were 47.4%, 47.4%, 44.7%, 39.3%, and 32.1%, respectively. In multivariate analyses, baseline BCR-ABL1 mutation status was significantly associated with cytogenetic and molecular responses. Common treatment-related adverse events included skin hyperpigmentation, hypertriglyceridemia, proteinuria, and severe thrombocytopenia. Conclusions Olverembatinib was well tolerated, with significant antileukemic activity in adults with TKI-resistant CML-CP and CML-AP, especially those with the T315I mutation. Trial registration : The phase 1 trial is registered at CTR20220566, and the two single-arm, open-label phase 2 studies are registered at ClinicalTrials.gov: NCT03883087 (CML-CP) and NCT03883100 (CML-AP).
The Neurodevelopmental Gene <i>MSANTD2 B</i>elongs to a Gene Family Formed by Recurrent Molecular Domestication of <i>Harbinger</i> Transposons at the Base of Vertebrates
Authors: Ema Etchegaray, Dominique Baas, Magali Naville, Zofia Haftek-Terreau, Jean Nicolas Volff
Journal: Molecular Biology and Evolution (2022)

Abstract The formation of new genes is a major source of organism evolutionary innovation. Beyond their mutational effects, transposable elements can be co-opted by host genomes to form different types of sequences including novel genes, through a mechanism named molecular domestication. We report the formation of four genes through molecular domestication of Harbinger transposons, three in a common ancestor of jawed vertebrates about 500 million years ago and one in sarcopterygians approx. 430 million years ago. Additionally, one processed pseudogene arose approx. 60 million years ago in simians. In zebrafish, Harbinger-derived genes are expressed during early development but also in adult tissues, and predominantly co-expressed in male brain. In human, expression was detected in multiple organs, with major expression in the brain particularly during fetal development. We used CRISPR/Cas9 with direct gene knock-out in the F0 generation and the morpholino antisense oligonucleotide knock-down technique to study in zebrafish the function of one of these genes called MSANTD2, which has been suggested to be associated to neuro-developmental diseases such as autism spectrum disorders and schizophrenia in human. MSANTD2 inactivation led to developmental delays including tail and nervous system malformation at one day post fertilization. Affected embryos showed dead cell accumulation, major anatomical defects characterized by impaired brain ventricle formation and alterations in expression of some characteristic genes involved in vertebrate nervous system development. Hence, the characterization of MSANTD2 and other Harbinger-derived genes might contribute to a better understanding of the genetic innovations having driven the early evolution of the vertebrate nervous system.
Acrokeratosis Paraneoplasticao of Bazex
Authors: S E Handfield-Jones, C N A Matthews, J P Ellis, K B Das, D H McGibbon
Journal: Journal of the Royal Society of Medicine (1992)

Bazex disease is one of the rarer cutaneous paraneo-plastic syndromes. It is characterized by psoriasiform changes on the digits, and in some patients spread to the ears, nose and in later stages to the limbs and trunk. The associated malignancy is typically a squamous cell carcinoma of the upper aerodigestive tract. We review the literature regarding acrokeratosis paraneoplastica of Bazex and report three cases which illustrate both the typical and some of the less common changes that are seen in the condition.